Proper environmental stimuli are required to maintain homeostasis of organs and living organisms, whereas excess stressors disrupt such homeostasis. The underlying mechanism involves in nuclear factors and gene transcription, where histone acetyltransferases (HATs) play an essential role. The enzyme p300 is a representative HAT that is essential for maintenance of the organ function of heart and brain, while it is also implicated in the pathogenesis. Thus, it is an essential biological question how p300 activity is influenced by environmental and intrinsic factors, such as stress, to mediate physiology or pathophysiology.
The inventors have previously reported that a unique pool of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activate p300, when GAPDH is oxidized/S-nitrosylated and translocated with E3 ubiquitin-protein ligase (Siah1) into the nucleus upon exposure to stressors: in this cascade, only a few percentage of GAPDH converted to a signaling molecule due to this specific posttranslational modification, and overall change in cytosolic and glycolytic GAPDH is negligible.
It has long been noted that the cognitive impairments in patients with schizophrenia point to dysfunction of the frontal lobe. These abnormalities are found throughout the lifespan of affected individuals, suggesting a neurodevelopmental basis, which is consistent with alterations in frontal lobe structure in some cases. At autopsy, neuropathology in schizophrenia affecting synaptic and cellular integrity has directed an increasing focus on prefrontal-dependent behaviors in preclinical models for this disease.
Because cortical asynchrony can contribute to the kinds of cognitive deficits found in patients, the failure of mechanisms needed for synchronous cortical activity, such as dysfunction of interneurons, are of particular interest. In that context, studies on autopsied brains from patients with schizophrenia show a decrease in parvalbumin immunoreactivity, a relevant marker for fast-spiking interneurons that regulate synchonous cortical activity. One possible cause of impaired integrity affecting that interneuron population comes from evidence that decreased parvalbumin immunoreactivity is elicited by oxidative stress in mouse models relevant to schizophrenia. Further supporting such a basis for prefrontal dysfunction, analysis of cerebrospinal fluid from recent-onset patients with schizophrenia has indicated the presence of oxidative stress.
Stress is known to affect all of the organ systems of the body. In another example, the heart develops hypertrophy to pathological stressors of various heart diseases, which can further progress to failure. Heart hypertrophy and failure is a leading cause of death, imposing an enormous burden to the society in the United States. Inhibition of stress induced heart disorders, such as hypertrophy, would be invaluable for prevention and treatment of cardiomyopathy and heart failure.
There exists, therefore, a critical need for new therapies for treatment of oxidative stress induced disorders, including major mental illnesses such as schizophrenia, mood disorders, and addiction, as well as disorders of other organs, such as heart.